INTRODUCTION

                There are many mental diseases that lead to a medical syndrome known as Dementia.  Syndrome is defined as signs and symptoms that result from, and/or associated with a particular disease.  Different syndromes occur with different mental diseases as well as with normal aging and physical diseases.  During the twentieth century, death certificates of mental disease patients showed “SENILE DEMENTIA” as the cause.  This convenient Dementia umbrella misrepresented a syndrome as oppose to a disease as the cause of death.  This illustrated the difficulty associated with understanding, diagnosing, and communicating different mental diseases. 

                This article discusses one of these mental disease, namely Alzheimer’s Disease and its road to Dementia.  Figure 1 hypothesizes a roadmap for AD progressing to Dementia.  Due to many uncertainties and unknowns associated with AD, as well as other mental diseases, the steps in the map are not precise data but subjective views based on available evidence as noted along the way.

                Alzheimer’s Disease is simplified here into symptomatic and presymptomatic.  A symptomatic patient displays cognitive impairment ©.  A presymptomatic patient is cognitively unimpaired (CU).  An autopsy report (Braak & Braak -1991) provided evidence that tau tangles in the Entorhinal Cortex (EC) were so great at a very mild AD stage, that the disease must have started many years earlier.  Then the EC was reported (Teresa Gomez-Isla et. al. – 1996) to have a 30% loss of neurons in levels 1 & 2 at this very mild AD stage.  This evidence was confirmed in vivo (living humans) with PET Scans in 2014.  This confirmation accelerated presymptomatic research. 

FIGURE 1 DESCRIPTION

                N0. 1 Asymptomatic AD:  Potential candidates, who are cognitively unimpaired (CU) as well as those with genetic mutations become possible future AD patients.  They are in mid-life without a thought or awareness of future mental diseases in their life.  Why mid-life and ages 45 – 55?  Sselected by working backwards 20 years from the point of my wife’s (an ApoE4 carrier) was diagnoses of MCI. 

                 No. 2 Amyloid Aggregation:  AB42 aggregates accumulate during an assumed 10-year period. With unknown evidence, or its rate of accumulation, it reaches an uncertain point and triggers the start of Tau fibrils & tangles.  Bruce’s prevention hypothesis posits treating these patients with proven clinical trial monoclonal antibodies (MAB) – (Aducanumab, Gantenerumab, and Crenezumab). These MABs dissolve and remove AB42 from the brain and thereby prevent the start of fibrils and tangles and loss of EC neurons, thereby preventing AD for this cohort group.       

                No. 3 Fibrils & Tangles:  The mechanism that determines the AB42 aggregate level to start fibrils & tangles is unknown, as is the transition rate to cause the death of neurons (neurodegeneration), but it is thought to be a very short time. 

                No. 4: Neurodegeneration:  Evidence (Braak Stages – 2006 and S. Wegmann et. al. 2019) reports that AD neurodegeneration starts in the transentorhinal cortex (TEC) and the EC.  This would seem to be a treatment target for delay interventions, but uncertainty of brain reaction may necessitate additional research.  This presymptomatic period (Nos. 1 – 4) deals with CU patients where little evidence data is currently available.  However, an effort is underway to develop new biological biomarker tools. 

                Since the presymptomatic period is CU, Bruce posits to redefine Nos 1 and 2 as a separate disease that does not need to meet the FDA intervention market requirement of “Meaningful Cognitive Benefit” and then pursue approval of monoclonal antibodies to treat the Nos 1 & 2 cohort groups.

                No. 5 – Mild Cognitive Impairment (MCI): Symptomatic AD begins with a diagnosis of MCI and is the transition from CU to C along with the uncertainty as to the amount of neurodegeneration as well as the rate of the progressive decline.  My experience of 18 years of personal caregiving evidence indicate there is an initial normal lifestyle period where a delay intervention could be significant.  Thus far, this has been elusive. 

                No. 6 Mild Ad: Lifestyle is still normal with noticeable signs beginning to show. 

                No. 7 Moderate AD: Cognitive Impairment and neurodegeneration become noticeable.  Help with Activities of Daily Living (ADL) are beneficial and encouraged.  Neurodegeneration is realistically past the point of delay. 

                No. 8) Severe AD: Aging begins compounding the disease.  Help with ADL becomes more routine, but a patient’s desire for independence, ego, and social interaction is still evident. 

                No. 9 Dementia: This is not only the most difficult period but also the most controversial as brings together all mental diseases.  It is complicated by aging issues both physical and mental (neuropils begin to die in aging, neuropils are neuron clusters with very small or no axons).   Bruce posits dementia begins when a patient no longer can independently sustain ADL.

SUMMARY

                Bruce posits there is no cure once the AD reaches No. 7 and that interventions for delay at Nos, 4, 5, and 6 have uncertainties relative to the amount of neurodegeneration (neuron damage).  Therefore, prevention offer the best hope at Nos. 1 1nd 2, with No 3 being an uncertainty. 

             

               

       

       

              

      

            

           

               

By Bruce Bauer à author – ABC’S of ALZHEIMER’S DISEASE: A SHARED REALITY by ME and MY SHADOW

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